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Molecular and Cellular Biology, May 2001, p. 3025-3036, Vol. 21, No. 9
Department of Microbiology/Immunology, Kimmel
Cancer Institute, Thomas Jefferson University, Philadelphia,
Pennsylvania 19107
Received 12 December 2000/Accepted 2 February 2001
The function of BAD, a proapoptotic member of the Bcl-2 family, is
regulated primarily by rapid changes in phosphorylation that modulate
its protein-protein interactions and subcellular localization. We show
here that, during interleukin-3 (IL-3) deprivation-induced apoptosis of
32Dcl3 murine myeloid precursor cells, BAD is cleaved by a caspase(s)
at its N terminus to generate a 15-kDa truncated protein. The 15-kDa
truncated BAD is a more potent inducer of apoptosis than the wild-type
protein, whereas a mutant BAD resistant to caspase 3 cleavage is a weak
apoptosis inducer. Truncated BAD is detectable only in the
mitochondrial fraction, interacts with BCL-XL at least as
effectively as the wild-type protein, and is more potent than wild-type
BAD in inducing cytochrome c release. Human BAD, which is
43 amino acids shorter than its mouse counterpart, is also cleaved by a
caspase(s) upon exposure of Jurkat T cells to anti-FAS antibody, tumor
necrosis factor alpha (TNF-
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.9.3025-3036.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Caspase Cleavage Enhances the
Apoptosis-Inducing Effects of BAD
), or TRAIL. Moreover, a truncated form
of human BAD lacking the N-terminal 28 amino acids is more potent than
wild-type BAD in inducing apoptosis. The generation of truncated BAD
was blocked by Bcl-2 in IL-3-deprived 32Dcl3 cells but not in Jurkat T
cells exposed to anti-FAS antibody, TNF-
, or TRAIL. Together, these
findings point to a novel and important role for BAD in maintaining the
apoptotic phenotype in response to various apoptosis inducers.
*
Corresponding author. Mailing address: Department of
Microbiology/Immunology, Kimmel Cancer Institute, Thomas Jefferson
University, Philadelphia, PA 19107. Phone: (215) 503-4522. Fax: (215)
923-0249. E-mail: B_Calabretta{at}lac.jci.tju.edu.
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